Platelet integrin αIIbβ3 plays a key role in a venous thrombogenesis mouse model.

Adair, Brian D.; Field, Conroy O.; Alonso, José L.; Xiong, Jian-Ping; Deng, Shi-Xian; Ahn, Hyun Sook; Mashin, Eivgeni; Clish, Clary B.; van Agthoven, Johannes; Yeager, Mark; Guo, Youzhong; Tess, David A.; Landry, Donald W.; Poncz, Mortimer; Arnaout, M. Amin

Venous thrombosis (VT) is a common vascular disease associated with reduced survival and a high recurrence rate. VT is initiated by the accumulation of platelets and neutrophils at sites of endothelial cell activation. A role for platelet αIIbβ3 in VT is not established, a task complicated by the increased bleeding risk caused by partial agonists such as tirofiban. Here, we show that m-tirofiban, a modified version of tirofiban, does not agonize αIIbβ3 based on lack of neoepitope expression and the cryo-EM structure of m-tirofiban/full-length αIIbβ3 complex. m-tirofiban abolishes agonist-induced platelet aggregation while preserving clot retraction ex vivo and, unlike tirofiban, it suppresses venous thrombogenesis in a mouse model without increasing bleeding. These findings establish a key role for αIIbβ3 in VT initiation and suggest that m-tirofiban and compounds with a similar structurally-defined mechanism of action merit consideration as potential thromboprophylaxis agents in patients at high risk for VT and hemorrhage. Tirofiban is an inhibitor of platelet αIIbβ3 which may contribute to venous thrombosis. Here the authors developed a non-agonizing modified tirofiban, defined by its cryo-EM structure bound to platelet αIIbβ3 and elucidated the pathogenic role of αIIbβ3 in venous thrombogenesis.

VENOUS thrombosis; PLATELET aggregation inhibitors; TIROFIBAN; VASCULAR diseases; LABORATORY mice; BLOOD platelet aggregation

Nature Communications, 2024, Vol 15, Issue 1, p1

2041-1723

Academic Journal

10.1038/s41467-024-52869-3